Selective Toxicity of NSC73306 in MDR1-Positive Cells as a New Strategy to Circumvent Multidrug Resistance in Cancer

Abstract

ATP-binding cassette (ABC) proteins include the best known mediators of resistance to anticancer drugs. In particular, ABCB1 [MDR1/P-glycoprotein (P-gp)] extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. Attempts to overcome P-gp-mediated drug resistance using specific inhibitors of P-gp has had limited success and has faced many therapeutic challenges. As an alternative approach to using P-gp inhibitors, we characterize a thiosemicarbazone derivative (NSC73306) identified in a generic screen as a compound that exploits, rather than suppresses, P-gp function to induce cytotoxicity. Cytotoxic activity of NSC73306 was evaluated in vitro using human epidermoid, ovarian, and colon cancer cell lines expressing various levels of P-gp. Our findings suggest that cells become hypersensitive to NSC73306 in proportion to the increased P-gp function and multidrug resistance (MDR). Abrogation of both sensitivity to NSC73306 and resistance to P-gp substrate anticancer agents occurred with specific inhibition of P-gp function using either a P-gp inhibitor (PSC833, XR9576) or RNA interference, suggesting that cytotoxicity was linked to MDR1 function, not to other, nonspecific factors arising during the generation of resistant or transfected cells. Molecular characterization of cells selected for resistance to NSC73306 revealed loss of P-gp expression and consequent loss of the MDR phenotype. Although hypersensitivity to NSC73306 required functional expression of P-gp, biochemical assays revealed no direct interaction between NSC73306 and P-gp. This article shows that NSC73306 kills cells with intrinsic or acquired P-gpinduced MDR and indirectly acts to eliminate resistance to MDR1 substrates. (Cancer Res 2006; 66(9): 4808-15)

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

“…Overexpression of MDR1 in patient tumour tissue following chemotherapy is well documented, whereas increased expression of FZD1 has not been reported Norris et al, 1997;Blanc et al, 2003;Munoz et al, 2007). Moreover, attempts to overcome P-gp-mediated drug resistance in patients using specific inhibitors of P-gp has had limited success (Duhem et al, 1996;Ludwig et al, 2006). Hence, we measured the mRNA expression of FZD1 and MDR1 in 21 pre-(at diagnosis) and post-treatment (after one or more cycles of chemotherapy)-matched patient samples, including 10 relapsed and 11 non-relapsed patients.…”

“…A promising initial response of the tumour to chemotherapy by shrinking of the tumour volume is frequently observed, followed by appearance of multidrug resistant variants and chemoresistance (Duhem et al, 1996;Ludwig et al, 2006). The multiple mechanisms contributing to chemoresistance are only partially elucidated (Gottesman et al, 2002).…”

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…that in contrast to the export of toxic substrates, P-gp can directly sensitize MDR cells [15,21,40,43]. Interestingly, the structurally diverse MDR-selective compounds share the ability to chelate metal ions.…”

“…Interestingly, the structurally diverse MDR-selective compounds share the ability to chelate metal ions. In particular, there is a strong link between the thiosemicarbazone backbone and MDR selective toxicity, as exemplified by several isatin-β-thiosemicarbazones including NSC73306 (1a, Figure 1, upper left panel), NSC658339, NSC716765, NSC716766, NSC716768, NSC716771 and NSC716772 (for structures, see Table S1) [15,21,40,43,44]. In addition to these TSCs the pharmacogenomic approach also identified a benzothiazole (NSC693630, Figure 1, upper middle panel) as a candidate MDRselective agent [15].…”

“…In addition to the reported TSC compounds 1a [15,21,40,43,44], the N4 para tolyl derivative M A N U S C R I P T…”